Rebecca Segrave

A Randomized Trial of rTMS Targeted with MRI Based Neuro-Navigation in Treatment-Resistant Depression

The aim of this study is to investigate whether repetitive transcranial magnetic stimulation (rTMS) targeted to a specific site in the dorsolateral prefrontal cortex (DLPFC), with a neuro-navigational method based on structural MRI, would be more effective than rTMS applied using the standard localization technique. Fifty-one patients with treatment-resistant depression were randomized to receive a 3-week course (with a potential 1-week extension) of high-frequency (10 Hz) left-sided rTMS. Thirty trains (5 s duration) were applied daily 5 days per week at 100% of the resting motor threshold. Treatment was targeted with either the standard 5 cm technique (n=27) or using a neuro-navigational approach (n=24). This involved localizing the scalp location that corresponds to a specific site at the junction of Brodmann areas 46 and 9 in the DLPFC based on each individual subjects MRI scan. There was an overall significant reduction in the Montgomery–Asberg Depression Rating Scale scores over the course of the trial, and a better outcome in the targeted group compared with the standard localization group at 4 weeks (p=0.02). Significant differences were also found on secondary outcome variables. The use of neuro-navigational methods to target a specific DLPFC site appears to enhance response to rTMS treatment in depression. Further research is required to confirm this in larger samples, or to establish whether an alternate method based on surface anatomy, including measurement from motor cortex, can be substituted for the standard 5 cm method.

Concurrent Cognitive Control Training Augments the Antidepressant Efficacy of tDCS: A Pilot Study

BACKGROUND Major depressive disorder (MDD) is frequently associated with underactivity of the dorsolateral prefrontal cortex (DLPFC) which has led to this brain region being identified as an important target for the development of neurobiological treatments. Transcranial direct current stimulation (tDCS) administered to the DLPFC has antidepressant efficacy, however the magnitude of antidepressant outcomes are limited. Concurrent cognitive activity has been shown to enhance tDCS induced stimulation effects. Cognitive control training (CCT) is a new cognitive therapy for MDD that aims to enhance DLPFC activity via behavioral methods. HYPOTHESIS We tested the hypothesis that co-administration of DLPFC tDCS and CCT would result in a greater reduction in depressive symptomology than administration of tDCS or CCT alone. METHODS 27 adult participants with MDD were randomized into a three-arm sham-controlled between-groups pilot study comparing the efficacy of 2 mA tDCS + CCT, sham tDCS + CCT and sham CCT + 2 mA tDCS (5 sessions administered on consecutive working days). Blinded assessments of depression severity and cognitive control were conducted at baseline, end of treatment and a three week follow up review. RESULTS All three treatment conditions were associated with a reduction in depression severity at the end of five treatment sessions. However, only administration of tDCS + CCT resulted in sustained antidepressant response at follow up, the magnitude of which was greater than that observed immediately following conclusion of the treatment course. CONCLUSIONS The results provide preliminary evidence that concurrent CCT enhances antidepressant outcomes from tDCS. In the current sample, participants receiving concurrent tDCS and CCT continued to improve following cessation of treatment. The clinical superiority of a combined therapeutic approach was apparent even in a small sample and following a relatively short treatment course.

A double blind randomized trial of unilateral left and bilateral prefrontal cortex transcranial magnetic stimulation in treatment resistant major depression

OBJECTIVE A substantive body of research has demonstrated the efficacy of repetitive transcranial magnetic stimulation treatment (rTMS) in patients with depression. However, the parameters needed to optimize therapeutic efficacy remain unclear. The aim of this study was to investigate whether there is an advantage in efficacy of sequential bilateral rTMS compared to standard high-frequency left sided rTMS. METHOD Sixty seven patients with treatment resistant depression were included in a randomised double-blind sham controlled trial of sequential bilateral rTMS compared to standard high-frequency left sided rTMS and sham rTMS over a three-week period. The study also included a further three week comparison of the two active treatment conditions. The primary outcome variable was scores on the 17-item Hamilton Depression Rating Scale (HAMD). RESULTS In the three-week double-blind phase of the trial there was a greater antidepressant response to unilateral left sided rTMS compared with sham or bilateral rTMS. Across the full six weeks of active rTMS, there was also a consistent pattern of improved response in unilateral left compared to bilateral treatment. Response rates were low in both active groups. CONCLUSIONS This study does not support the hypothesis that sequential bilateral rTMS is more effective than unilateral high-frequency left-sided rTMS.

A study of the effectiveness of bilateral transcranial magnetic stimulation in the treatment of the negative symptoms of schizophrenia

BACKGROUND Repetitive transcranial magnetic stimulation (rTMS) is increasingly being investigated as a potential treatment for a number of psychiatric disorders, including schizophrenia. Previous rTMS studies have targeted the left-side prefrontal cortex (PFC) in the treatment of negative symptoms, with inconsistent findings. Some imaging evidence suggests right-sided or bilateral PFC involvement in negative symptoms, areas yet to be investigated for rTMS treatment. The study therefore aimed to assess the efficacy of bilateral high-frequency rTMS in the treatment of negative symptoms. METHODS A 2-arm double-blind randomized controlled trial was conducted with 20 patients with a diagnosis of schizophrenia or schizoaffective disorder, and moderate-to-severe treatment-resistant negative symptoms. Participants received a 3-week course of high-frequency bilateral rTMS or sham. Twenty trains (5 seconds duration) of 10 Hz rTMS at 110% of the RMT were administered to each PFC daily, 5 days a week. RESULTS No significant group or time differences in the Scale for the Assessment of Negative Symptoms (SANS) scores or cognitive outcomes were evident. However, a trend for greater reduction in scores on the autistic preoccupation scale of the Positive and Negative Symptom Scale for the active group compared to the sham group was observed (P = .05). CONCLUSIONS No substantial benefit of high-frequency bilateral rTMS was seen in the treatment of the negative symptoms of schizophrenia. Further research is required to explore whether rTMS may have benefits specific to particular cognitive or symptom domains.

Individualized Alpha Activity and Frontal Asymmetry in Major Depression

Lateralized differences in frontal alpha power in individuals with major depressive disorder (MDD) are thought to reflect an aberrant affective processing style. However research into anterior alpha asymmetry and MDD has often produced conflicting results. The current study aimed to investigate whether individualized alpha bandwidths provide a more sensitive measure of anterior alpha asymmetry in MDD than the traditional fixed 8–13 Hz alpha band. Resting EEG was recorded from 34 right-handed female participants (18 controls, 16 MDD). Each participants Individual Alpha Frequency was used to delineate a broad individualized alpha band and three individualized narrow alpha sub-bands: lower alpha1, lower alpha 2 and upper alpha. Activity within the broad and narrow individualized bandwidths and within the traditional fixed alpha band were used to compare a) controls and acutely depressed individuals and b) medicated and unmedicated MDD participants. Individualizing and subdividing the alpha bandwidth did not add appreciably to the sensitivity of anterior alpha asymmetry in MDD as no significant differences in lateralized alpha power between controls and MDD participants were observed in any alpha bandwidth. This finding was consistent under two reference schemes and across multiple scalp locations. Within the MDD group, antidepressant use was associated with significantly greater right than left hemispheric power in the lower alpha 1 band. The relevance of this finding is discussed in relation to the electrophysiological correlates of antidepressant medication use, lateralized differences in affective processing and treatment resistant MDD.

A study of the effectiveness of high-frequency left prefrontal cortex transcranial magnetic stimulation in major depression in patients who have not responded to right-sided stimulation

The objective of this study was to explore the response rate to high-frequency left-sided repetitive transcranial magnetic stimulation (rTMS) in patients who had failed to respond to right-sided low-frequency stimulation, and to investigate whether there was differential efficacy between stimulation at 5 or 10 Hz. Data from two randomized controlled trials were pooled. In both studies a group of patients were randomized to receive either 5- or 10-Hz left prefrontal rTMS after failing to respond to right-sided stimulation. These patients received blinded 5- or 10-Hz stimulation (but without a sham control) for a period of up to 4 weeks and outcomes were compared. There was a small but significant overall response to left-sided rTMS but no difference in response between the 5- and 10-Hz treatment conditions. There appears to be a significant but modest likelihood of response to left-sided TMS in patients who fail right-sided stimulation, but there is no difference in efficacy between 5- and 10-Hz stimulation.

Transcranial magnetic stimulation for depression after a traumatic brain injury: a case study.

Depression after a traumatic brain injury (TBI) is very common, yet there is a lack of evidence-based treatment options for people who experience depression after a TBI. Traditionally, a history of TBI has been considered an exclusion criterion for transcranial magnetic stimulation trials because of the increased risk of seizure after a TBI. We present what we believe to be the first case of a patient with depression after a TBI treated with transcranial magnetic stimulation.

Emotional valence modulates putative mirror neuron activity

Mirror neurons are thought to facilitate emotion processing, but it is unclear whether the valence of an emotional presentation (positive or negative) can influence subsequent mirror neuron activity. Participants completed a transcranial magnetic stimulation experiment that involved stimulation of the primary motor cortex, and electromyography recording from contralateral hand muscles. This was performed while participants viewed videos of either a static hand or a transitive hand action preceded by either a positive or negative stimulus. Corticospinal excitability facilitation during action observation was significantly greater following the presentation of negative (relative to positive) stimuli; this was evident for the first dorsal interosseous muscle (which was central to the observed grasp), but not for the abductor digiti minimi muscle. This study provides evidence that emotional valence can modulate mirror neuron activity, which may reflect an adaptive mechanism.

Deep brain stimulation in mental health: Review of evidence for clinical efficacy

Objective: There is increasing interest in the use of deep brain stimulation as a treatment for psychiatric disorders. In this review, we consider the evidence for the effectiveness of deep brain stimulation for psychiatric indications, with a primary focus on obsessive compulsive disorder and major depressive disorder. Methods: Case reports, case series and clinical trials where deep brain stimulation was primarily utilised in the treatment of a psychiatric disorder, including obsessive compulsive disorder, major depressive disorder, anorexia nervosa or an addictive disorder were identified. The evidence for the effectiveness of deep brain stimulation in the treatment of obsessive compulsive disorder and major depressive disorder was reviewed with studies clustered by the site of implantation. Results: The majority of identified manuscripts report small case series or single cases. A limited number of studies have reported some form of randomised or blinded stimulation comparison. All of these comparative reports have included small samples of subjects (less than 20 per study in total) compromising the feasibility of making statistical comparison between outcomes in the comparison phases. The two exceptions to this have been industry-sponsored studies conducted in the treatment of major depressive disorder. However, both were stopped prematurely due to concerns about poor efficacy. Conclusions: There is insufficient evidence at this point in time to support the use of deep brain stimulation as a clinical treatment for any psychiatric disorder outside of research and programmes where formal outcome data are being systematically collated. While some promising initial data exist to support its potential efficacy for a number of psychiatric conditions, further research is required to establish optimal implantation targets, patient characteristics associated with positive therapeutic outcomes and optimal deep brain stimulation parameters and parameter-programming methods.

A study of intensity dependence of the auditory evoked potential (IDAEP) in medicated melancholic and non-melancholic depression

BACKGROUND Major Depressive Disorder is widely recognised to be a heterogeneous syndrome with numerous depressive phenotypes, one of which is melancholic depression. Patients with melancholic depression exhibit treatment responses and outcomes that differ from patients with non-melancholic depression. The current study aimed to assess whether differences existed between melancholic and non-melancholic subtypes of depression, as measured by the event related potential, intensity dependence of the auditory evoked potential (IDAEP). METHODS IDAEP was assessed in 14 melancholic and 13 non-melancholic depressed subjects and 14 controls. RESULTS The melancholic patients had a significantly shallower IDAEP slope than the non-melancholic patients not explained by depression severity or age. LIMITATIONS Antidepressants were taken by all patients in this study and the effect of continual use of these drugs on the IDAEP slopes has yet to be confirmed. CONCLUSIONS These results provide support for neurobiological differences between melancholic and non-melancholic depressive subtypes. Melancholic depression may be characterized by ongoing over function of the serotonin system in spite of medication treatment.